Summary:
In this study, we use an experimental imaging–genetics approach for investigating the genetic underpinnings of brain atrophy in Alzheimer’s disease. We successfully combined state-of-the-art imaging–genetics methods and experimental gene expression data to uncover biology in brain atrophy. The experimental paradigm highlighted a significant role of tribbles pseudokinase 3 (TRIB3) in modulating the typical pattern of Alzheimer’s brain pathology. This result corroborates through rigorous data-driven statistical methods evidence emerging from previous studies about the role of TRIB3 in modulating known mechanisms of neurodegeneration, such as neuronal death, cellular homeostasis, and interaction with established genes causing autosomal dominant Alzheimer’s disease: APP and PSEN1. The developed integrated statistical–experimental methodology could serve as a roadmap for investigations in other disorders.